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| Status |
Public on Sep 25, 2023 |
| Title |
Transcriptional heterogeneity overcomes super-enhancer disrupting drug combinations in multiple myeloma [ATAC-seq] |
| Organism |
Homo sapiens |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
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| Summary |
Multiple myeloma (MM) is a malignancy that is often driven by MYC and that is sustained by IRF4, which are upregulated by super-enhancers. IKZF1 and IKZF3 bind to super-enhancers and can be degraded using immunomodulatory imide drugs (IMiDs). Successful IMiD responses downregulate MYC and IRF4; however, this fails in IMiD-resistant cells. MYC and IRF4 downregulation can also be achieved in IMiD-resistant tumors using inhibitors of BET and EP300 transcriptional coactivator proteins; however, in vivo these drugs have a narrow therapeutic window. By combining IMiDs with EP300 inhibition, we demonstrate greater downregulation of MYC and IRF4, synergistic killing of myeloma in vitro and in vivo, and an increased therapeutic window. Interestingly, this potent combination failed where MYC and IRF4 expression was maintained by high levels of the AP-1 factor BATF. Our results identify an effective drug combination and a previously unrecognized mechanism of IMiD resistance.
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| Overall design |
To determine the chromatin accesibility changes induced by the ImmunoModulatory imide Drug (IMiD) pomalidomide (POM) and the EP300 inhibitor GNE-781 (G781) alone or in combination on multiple myeloma JJN3 and KMS11 cells with (+BATF) or with out (+eGFP) BATF overexpression.
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| Contributor(s) |
Welsh SJ, Barwick BG, Bergsagel PL |
| Citation(s) |
37767768 |
| |
| Submission date |
Sep 25, 2023 |
| Last update date |
Jan 25, 2024 |
| Contact name |
Benjamin G Barwick |
| E-mail(s) |
benjamin.barwick@emory.edu
|
| Phone |
(404) 285-2964
|
| Organization name |
Emory University
|
| Department |
Hematology and Medical Oncology
|
| Lab |
Barwick Lab
|
| Street address |
1365 Clifton Rd. NE WCI-C 4th Floor Benches 36-37
|
| City |
Atlanta |
| State/province |
GA |
| ZIP/Postal code |
30322 |
| Country |
USA |
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| Platforms (1) |
| GPL21290 |
Illumina HiSeq 3000 (Homo sapiens) |
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| Samples (8)
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| This SubSeries is part of SuperSeries: |
| GSE244003 |
Transcriptional heterogeneity overcomes super-enhancer disrupting drug combinations in multiple myeloma |
|
| Relations |
| BioProject |
PRJNA1020836 |
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